Neural tube defects (NTDs) occur in about 1/1000 births in the United States. Though much has been learned from these defects, and folate treatment has significantly reduced their occurrence, much remains to be learned. It has been estimated that perhaps 50% or more of all NTDs have a genetic cause though the genes responsible generally are not known. There is thought to be an influence of environmental effects on those genetic deficits, but at what level is not known. This program project will use several models to examine these questions with the goal of increasing knowledge of the genetic component of NTDs. The project brings together six investigators at Duke University who will work collaboratively on this problem. The six projects include: (1) John Klingensmith, who will study the basis of fully-penetrant NTD phenotypes in mice mutant for the BMP antagonist noggin. He will misexpress mutant BMP receptors via the Cre/lox system to determine how BMP signaling controls dorsal development. (2) Erik Meyers who will follow preliminary loss of function studies indicating that a balance between the BMP and Fgf signaling families is required for normal neural tube patterning and closure. Cre/loxP analysis will ectopically localize either increased expression or decreased expression of these components as a test of function. (3) David McClay who will examine quantitative adhesion changes during normal neural tube closure and compare those data with homozygotes having a fully penetrant NTD and heterozygotes with no visible abnormal phenotype. The hypothesis is that the heterozygotes will nevertheless have a measurable deficit in adhesion. (4) Dan Kiehart who will study dpp mutants (the BMP homolog in flies) that cause a failure in dorsal closure. This process has many cellular morphogenetic properties that are similar to neural tube closure in mammals. He will screen for mutants in a search for genes whose products are required for TGFbeta signaling function including cellular aspects of morphogenesis. (5) Elwood Linney who will use a new promoter trap retroviral vector that his laboratory constructed to identify and isolate genes expressed during neural tube development in zebrafish. (6) Marcy Speer, who, based on the other components of this PO1, will examine the hereditary factors predisposing humans to NTDs, with the ultimate aim of characterizing interactions between genes and between genes and the environment, eventually leading to mechanisms for the prevention of these frequent birth defects.